The goal of this project has been to examine the central effects of changes in reproductive endocrine function occurring in the context of hypogonadism. Investigations have been primarily focused on the characterization of affective disorders occurring during the perimenopause and midlife, the identification of the role of gonadal steroids in these mood disorders, and the examination of the neuroregulatory consequences of the presence and absence of gonadal steroids. Finally, the information obtained by these protocols will help identify the predictive utility of endocrine measures in perimenopausal depression and help define the role of hormonal therapies in mood disorders occurring at midlife in men and women. Findings to date include: 1) 11 episodes of depression have been documented in nine of 29 asymptomatic women who were followed for an average of 5.3 years until the occurrence of at least six months of amennorrhea; nine episodes occurred within 12 months of the last menstrual period and two occurred before the onset (six and 12 months) of menstrual cycle irregularity. Six of the nine women who became depressed during the study had no prior depressive episodes whereas of the nine women with a past history of depression prior to study entry, only three developed a depression during the study; 2) a significant decrease in plasma FSH levels was observed in 18 perimenopausal depressed women who experienced a spontaneous and clinically significant improvement in their depression (50% decline in CES-D scores) during a six week observation period; 3) a significant improvement in depression severity scores and libido (but not measures of cognitive function) was seen after DHEA administration in 23 men and 26 women with midlife-related depression; 4) neither gender nor plasma DHEA levels predicted therapeutic response to DHEA administration in midlife-related depression; 5) no significant effects of DHEA was seen on vascular motility or on plasma and urinary markers of bone metabolism; 6) the maintenance of antidepressant effectiveness and preliminary evidence of an increase in bone density (as measured by DEXA scan) was documented in nine subjects who have received DHEA for one year; and 7) two depressed perimenopausal women have experienced a remission of their depression during participation in a double-blind placebo-controlled trial of estradiol, phytoestrogens, and SERMs. In a study involving the induction of hypogonadism in men and women with GnRH agonists, we have observed the hypogonadal state to be associated with the following: 1) decreased measures of sexual function in both men and women, with a restoration of normal sexual function during gonadal steroid replacement in 20 men with testosterone but not in 20 women with either estradiol or progesterone; 2) baseline ratings of sexual functioning (high/low) in men predict response to hypogonadism and testosterone replacement; 3) no significant effects on mood and behavioral symptoms in men (with the exception of libido and hot flushes) on a group basis; however, clinically significant depression-like symptoms were observed in 10% of the men; 4) elimination in women of cognition activated regional cerebral blood flow (O15 3D PET scans) in the dorsolateral prefrontal cortex and a disruption of the connectivity between the hippocampal formation and the dorsolateral prefrontal cortex compared to either estradiol or progesterone replacement; 5) no differences in cognitive test performance (during hypogonadism or estradiol replacement) but a significant improvement in the performance of tests of motor dexterity and verbal fluency during progesterone replacement compared to baseline and hypogonadal conditions. Finally, in collaboration with NICHD we have observed that women with Turner's Syndrome have significantly higher scores on measures of shyness (but not depression or anxiety) than asymptomatic controls and that women with endometriosis receiving raloxifene do not report a significantly increased frequency of mood problems compared to those on placebo.